METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53‐wild‐type cells.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40–50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild‐type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild‐type p53 and suppresses tumor growth only in p53‐wild‐type (p53‐WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM‐induced CRC growth in mouse models with the intestinal epithelial cell‐specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53‐WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6A‐YTHDF2‐dependent pri‐miR‐6769b/pri‐miR‐499a processing. Biosynthetic mature miR‐6769b‐3p and miR‐499a‐3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53‐WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53‐dependent cancer growth inhibition, which could be targeted for therapy in p53‐WT CRC. Synopsis: METTL14 specifically counteracts colorectal tumorigenesis in p53‐wild‐type cells by attenuating aerobic glycolysis. METTL14 decreases SLC2A3 and PGAM1 expression via selectively promoting m6A‐YTHDF2‐dependent pri‐miR‐6769b and pri‐miR‐499a processing. METTL14 is transcriptionally activated by wild‐type p53 and inhibits progression of p53‐wild‐type colorectal cancer (CRC).METTL14‐mediated m6A modification promotes YTHDF2‐dependent processing of pri‐miR‐6769b and pri‐miR‐499a.miR‐499a‐3p and miR‐6769b‐3p target SLC2A3 and PGAM1, respectively, thereby inhibiting glycolysis in p53‐wild‐type CRC.METTL14 expression inversely correlates with poor prognosis in p53‐wild‐type colorectal cancer. [ABSTRACT FROM AUTHOR]